Diabetic neuropathy causes pain. C nociceptors are neural instruments for reception of noxious stimuli and for transmission of impulses decoded as pain sensation in the brain. They also mediate antidromic inflammation. C nociceptor dysfunction is a main cause of spontaneous pain, hyperalgesia for mechanical or thermal stimuli, and neurogenic inflammation. Following discovery of hyperexcitable C nociceptors in patients, these units have become a focus for investigation in painful neuropathy. Recent scientific advances enlighten understanding of nociceptor function and disease, and provide new methods for their investigation in man. These include: a) biophysical differentiation of subtypes of human C units, b) identification of specific voltage and heat sensitive ion channels, and their blockers, in the excitable membranes of C nociceptor neurons (animals), c) discovery of an insensitive nociceptor subtype, d) characterization of receptor properties of C nociceptors from human muscle, e) objective measurement through skin microdialysis or thermography of vascular responses to C antidromic excitation, f) recognition of abnormal catecholamine sensitivity of surviving nociceptor axons in (animal) neuropathy, and g) discovery of secondary central neuronal windup and sensitization (animals). Upgrading our research on pain, we will apply a fresh paradigm to investigate nociceptor status in diabetic neuropathy patients and normal volunteer controls. We propose a) to further characterize subtypes of C units serving skin, and also muscle, through in vivo biophysical and physiological measurements in patients and volunteers. b) We will measure baseline excitability of C nociceptor subtypes in diabetic neuropathy patients, particularly in those with the ABC syndrome of nociceptor sensitization, compared to experimentally sensitized (capsaicin) nociceptor subtypes in volunteers. c) We will study the effects of catecholamines upon excitability or subtypes of C nociceptors in patients and in areas of hyperalgesia in sensitized volunteers. d) Finally, we will indirectly test central neurons of diabetics and volunteers with sensitized nociceptors for presence of secondary sensitization hypothetically maintained by the primary nociceptor source.